Obesity is a major contributing risk factor to leading causes Of death in the United States including cardiovascular disease, diabetes, and certain cancers (breast, colorectal, and genitourinary). These obesity associated diseases have an enormous impact on many surgical specialties. Indeed, operative treatment of these ailments or their sequelae has very substantially shaped the present day practice Of surgery. Recent advances in the scientific understanding of weight homeostasis have generated considerable hope that additional approaches can be developed to regulate body weight and help diminish the threat of obesity to the health of many Americans. In the past year exciting discoveries have demonstrated that the pro- opiomelanocortin (POMC) derived melanocortin peptides and the melanocortin-4 receptor (MC4R) play a key role in the hypothalamic control of body weight. These findings suggest that the melanocortins act as important hormonal messengers that signal satiety. Recently, additional complexity surrounding the function Of the melanocortins in weight homeostasis has been uncovered with the isolation of a novel antagonist of these peptides named agouti gene-related protein (AGRP). This proposal is directed towards the study of the role of melanocortins and the MC4R in the hypothalamic control of body weight. We propose to use in situ hybridization and immunohistochemistry to delineate the hypothalamic circuitry of the MC4R, POMC prohormone and three elements which we hypothesize antagonize the anorexic action of melanocortins, AGRP, neuropeptide Y, and the neuropeptide Y Y5 receptor. In order to gain insight into these interactions, normal rodents, fasted rodents, and several rodent models of obesity (fatty Zucker rat and obese and tubby mice) will be examined. Secondly, we propose to aid the development of drugs designed to control body weight by performing three dimensional receptor modeling and site-directed mutagenesis of the human MC4R. Thirdly, we propose to examine the sequence of the coding region of the human MC4R gene of obese patients to determine if receptor variants underlie some human obesity. Finally, we propose to examine the mechanisms through which AGRP antagonizes the melanocortins by characterizing the action of recombinant AGRP.